Plasma cell myeloma (or multiple myeloma or MM) accounts for approximately 1.3% of neoplastic diseases and 17.9% of hematologic cancers (Globocan-EU28, 2012, see http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx). The median age at diagnosis is approximately 70 years; 37% of patients are younger than 65 years, 26% are between the ages of 65 and 74 years, and 37% are 75 years of age or older. Plasma cell myeloma (PCM) is slightly more common in men than in women and is twice as common in African-Americans compared to Caucasians.
PCM remains incurable despite conventional and high-dose chemotherapy.
Despite improvements in the therapeutic armamentarium, curative therapy does not exist, and all patients eventually experience relapse. The prognosis is particularly poor for patients with relapsed and refractory disease, with survival estimates ranging from 6 to 9 months. In addition to resistance to the currently available therapies, patients who progress failing multiple novel agents have limited treatment options, because of the presence of co-morbid conditions due to the primary disease or to prior therapies.
New, effective and well tolerated agents for the treatment of relapsed myeloma are therefore still needed.
In the 1960s, melphalan+prednisone (MP) therapy was introduced for the treatment of MM, which extended the median survival from approximately 1.5 years to 2 years. Since the late 1990s, high-dose melphalan therapy (200 mg/m2) followed by autologous stem cell transplantation (ASCT) has been applied after induction therapy with vincristine+adriamycin+dexamethasone (VAD) in patients younger than 65 years of age, which resulted in the further improvement of survival to 5 years. Consequently, induction therapy+ASCT has been regarded as a standard therapy for younger patients with good health condition, and MP therapy was regarded as a standard of care for elderly patients of 65 years of age or older. Autologous hematopoietic stem cell transplantation (HSCT) involves the intravenous (IV) infusion of autologous stem cells to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective.
In the early phase of the 21st century, novel agents such as thalidomide, bortezomib, and lenalidomide have entered into clinical practice and become key drugs in the treatment of MM.
Bortezomib-based regimens are now used as induction therapy before ASCT in transplant-eligible patients, and MP+thalidomide, MP+bortezomib, and lenalidomide+dexamethasone are the widely used regimens for transplant-ineligible patients. Several clinical studies have shown an improvement of overall response rate and progression-free survival (PFS) in both transplant-eligible and transplant-ineligible patients by incorporating novel agents into antimyeloma therapy. Multiple myeloma remains an incurable disease despite the availability of multiple treatments such as conventional and high-dose chemotherapy. The lack of available effective and safe therapies to treat resistant/relapsing tumors constitutes a critical and ongoing unmet medical need.
Proteasome inhibition has in fact assumed a central role in the management of MM, due to the effectiveness of this treatment strategy and a manageable safety profile.
Bortezomib is used at every stage of treatment for MM, from frontline combination therapy, to re-treatment for relapsed disease, therapy for refractory disease, and as induction, consolidation, and maintenance therapy before and after auto HSCT.
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitinproteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma. Therefore, MM cells undergo apoptosis more readily when protein homeostasis is disrupted (Adams J., Nat. Rev. Cancer, 2004, 4, 349-360). This confers selectivity to these agents and a therapeutic index that is non-cell cycle specific (unlike cytotoxic chemotherapeutic agents, which affect all dividing cells and derive their selectivity from the fact that a larger fraction of the cancer cells are undergoing mitosis at any given time, compared to normal cells).
Bortezomib (VELCADE®) is a dipeptide boronic acid and chymotryptic site-selective inhibitor of the 20S proteasome. It has been approved in the U.S for the treatment of patients with multiple myeloma and for the treatment of patients with mantle cell lymphoma. It has been approved in Europe as monotherapy for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.
In combination with melphalan and prednisone, bortezomib is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant.
In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease (Merin N M, Kelly K R. Pharmaceuticals (Basel). 2014 Dec. 24; 8(1):1-20).
The boron atom in bortezomib binds the catalytic site of the 26S proteasome with high affinity and specificity. In normal cells, the proteasome regulates protein expression and function by degradation of ubiquitinylated proteins, and also cleanses the cell of abnormal or misfolded proteins.
Carfilzomib (KYPROLIS™) is a tetrapeptide epoxyketone proteasome inhibitor that irreversibly binds to the N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. The chemical name for carfilzomib is (2S)—N—((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)4-phenylbutanamido)-4-methylpentanamide.
Carfilzomib had antiproliferative and proapoptotic activities in vitro in solid and hematologic tumor cells. In animals, carfilzomib inhibited proteasome activity in blood and tissue and delayed tumor growth in models of multiple myeloma, hematologic, and solid tumors. Carfilzomib has been approved by US FDA for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy.
Proteasome inhibitors are currently studied for the treatment of relapsed/refractory multiple myeloma, see the review by Lonial and Boise, Oncology Journal, November 2011.
Melphalan (ALKERAN®, L-sarcolysin) is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents. An alkylating agent works by adding an alkyl group (CnH2n+1) to DNA. In particular it binds the alkyl group to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring, thus producing linkages between strands of DNA. This chemical modification inhibits DNA synthesis and RNA synthesis, which are biological functions essential for the cells to survive. These chemical modifications therefore cause cytotoxicity in both dividing and non-dividing tumor cells.
Structurally melphalan is a phenylalanine derivative of mechlorethamine.
Roneparstat (proposed INN, previously also designated as 100NA-RO.H or SST0001 or G4000) is a modified heparin derivative that is 100% N-desulphated, N-reacetylated and glycol split (Casu B et al., Pathophysiol Haemost Thromb, 2008; 36:195-20; Naggi A et al., J Biol Chem. 2005; 280:12103-13). These modifications abolish the anticoagulant activity at the doses expected to achieve a significant enzyme inhibition, while any possible residual anticoagulant activity in the high dose range is devoid of any clinical relevance, but enhance the inhibition of heparanase. Roneparstat has shown efficacy in preclinical models of cancers and recently entered Phase I clinical trial in patients with multiple myeloma. Roneparstat markedly decreased the extent of albuminuria and renal damage in mouse models of diabetic nephropathy. This has an important clinical relevance since renal impairment affects between 15-40% of multiple myeloma patients (JCO 2010; 28: 4976).